The present invention relates to a series of new pyridine derivatives, their preparation procedures, their use as cardioprotective agents, and the pharmaceutical compositions containing said derivatives. More particularly, the object of the present invention is constituted by pyridine derivatives of general formula (I), in which 
X represents H, NO2, OH, CN, F, Br, Cl, CF3, xe2x80x94NHxe2x80x94COxe2x80x94CH3, 2,3-Cl2, 2,3-(OCH3)2, 4-Cl, 3-NO2 and 2-[CHxe2x95x90CHxe2x80x94COOxe2x80x94C(CH3)3], and the fused cycle 2,3-oxadiazole [2,3-(xe2x95x90Nxe2x80x94Oxe2x80x94Nxe2x95x90)];
Y represents an alcoxycarbonyl fragment R3OOCxe2x80x94, where R2 can be H, a small alkyl group, 2-methoxyethyl, 2-tetrahydrofurfuryl or 5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl;
R represents H, an small alkyl group or, alternatively, the following fragments: 2-methoxyethyl, 2-(benzyl-methylamino)ethyl, 2-tetrahydrofurfuryl, 5-oxotetrahydrofurfuryl, 3-[(4,4-diphenyl)-piperidinyl]propyl, (R)-1-benzyl-3-piperidinyl, 2-(N-benzyl-(N-phenylamino)ethyl, (S)-1-benzyl-3-pirrolidinyl, 2-[(4-diphenylmethyl)-1-piperazinylethyl, 3-phenyl-2-propenyl, dually-amino-alkyl, 2-(N-morpholino)ethyl or 1,3-di(N-morpholino)isopropyl
Rxe2x80x2 represents CH3, CN or xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NH2, as well as the corresponding optical isomers, and the pharmaceutically acceptable salts of the said compounds.
As non-limiting examples, the following compounds corresponding to formula (1) of the present invention can be mentioned:
4-(2,3-Dichloro-phenyl)-2,6-dimethyl-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-fluorophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Acetylaminophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
2,6-Dimethyl-4-(3-hydroxyphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
2,6-Dimethyl-4-phenyl-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5xe2x80x94(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3,5-di(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
4-(3-Cyanophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(4-Chloro-3-nitrophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Bromophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3,5-di(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-trifluoromethylphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(2-Chlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran)-2-ylmethyl) ester
2,6-Dimethyl-4-(2-trifluoromethylphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2,3-dimethoxyphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Chlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(5-oxotetrahydrofuran-2-ylmethyl) ester
(S)-2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
(R)-2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(2-Bromophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3-isopropyl ester 5-(2-methoxyethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-isobutyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid dimethyl ester
4-[2-(2-tert-Butoxycarbonylvinyl)-phenyl]-2,6-dimethyl pyridine-3, 5-dicarboxylic acid diethyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(N-methylbenzylamino)ethyl ester
4-(2,3-Dichlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid
2-(2-Aminoethoxy)methyl-4-(2-chlorophlnyl)-6-methyl pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-methoxyethyl) ester 5-(3-phenyl)propen-2-yl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-dimethylaminoethyl) ester 5-methyl ester (dihydrobromide)
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-diethylaminoethyl) ester 5-methyl ester (dihydrochloride)
2,6-Dimethyl-4-phenylpyridine-3, 5-dicarboxylic acid dimethyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(3-dimethylaminopropyl) 5-methyl ester (dihydrochloride).
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(N-morpholino)ethyl ester (dihydrochloride)
2,6-Dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-[1,3-di(N-morpholine)isopropyl] ester trihydrochloride
The compounds corresponding to formula (Ia, examples 1-30) could, in a general method, be prepared by oxydation of 1,4-dihydropyridines corresponding to formula (II). In some cases, when Xxe2x95x902xe2x80x94NO2, many dihydropyridines II could be rather unstable, so products had to be obtained through Ib and III, (Scheme I), allowing the preparation of new derivatives Ic. In the scheme, X, R and Rxe2x80x2 are like have been defined before, and Rxe2x80x3, although differentiated for clarity in the scheme, should be taken as defined for R. 
The 1,4-dihydropyridine derivatives (II) are either already known, or could be prepared by the standard procedures described in the literature.
As oxydation agents for preparation of the compounds (a) it is possible to use all described for standard oxydation procedures, as oxygen, NaNO2/NOAc, NaNO2/HCl, HNO3, Fe(NO3)3 or Cu(NO3)2, Br2+NaAcO, CrO3, sulphur, KMnO4, chloranyl or o-chloranyl, 2,3-dihydro-5, 6-dicyano-1,4-benzoquinone (DDQ), Pd/C, pyridinium chlorochromate adsorbed on alumina (PCC/Al2O3), pyridinium dichromate, MnO2, etc. Controlled ester hydrolysis of Ia, to produce Ib, activation through III and esterification to Ic are described in the present report.
The pharmaceutically acceptable salts obtained by addition of acid to the compounds (I) are prepared by conventional methods, by treatment of a solution or suspension of the free base (I) with one or two equivalents of a pharmaceutically acceptable acid, either organic or inorganic. To give some examples, it is possible to mention the following acids: hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, lactic, p-toluenesulphonic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulphonic and benzenesulphonic. The obtained salts can show some advantages, particularly in relation with higher solubility in polar solvents as water. This can facilitate the preparation of galenic forms requiring the administration of the product dissolved in water.
The mixtures of diastereomers or enantiomers can be separated using the differences of physico-chemical properties of the products, through the usual methods as fractional crystallisation, chromatography, reactions with asymmetric induction, or by the action of enzymes or micro-organisms.
The present inventors had put in evidence the fact that the pyridine compounds with formula (I), according the present invention, have a cardioprotective activity and thus, can be used as cardioprotective agents. In addition, another object of the present invention consists in pharmaceutical preparations containing at least, one compound of formula (I), as previously defined, or one of its pharmaceutically acceptable salts.
The compounds of formula (I) according the invention can be administered alone but, in general, they would be administered as a mixture with a selected pharmaceutical excipient, depending of thr route of administration and the standard pharmaceutical practice. As an example, they can be administered by oral route, either in the form of tablets, containing excipients as starch or lactose, or in capsules, either alone or mixed with excipients, or in the form of syrups or suspensions, containing colour or aromatic substances. They can also be injected by parental route, as by example, by intramuscular, intravenous or subcutaneous route. When administered by parenteral route, they will be preferably used in the form of sterile aqueous solution, which can contain other solutes, as for instance, salt or glucose, to render the solution isotonic.
The pharmaceutical compositions according the invention could contain a quantity of any of the products with general formula (I) in the way the level of the administered dose being between 0.01 and 20 mg/kg. The daily dose of the active principle depends of the administration route. In general, an oral dose between 5 and 1000 mg/day will be used.
While when administered intramuscular route, the product can be given in one dose or divided up to three doses, when intravenously administered the product can be included into a dropwise system, for continuous supply. There will be necessarily variations depending of the weight and conditions of the patient, as well as of the administration route chosen.
In that way, the pharmaceutical compositions according the present invention, can be used as new drugs for the prevention or treatment of cardiovascular diseases, as cardiomyopaties, myocardium infarction, angina, cardiac failures, coronary vasospasm, valvular heart disease, etc.